Vagal tone: effects on sensitivity,motility, and inflammation

The vagus nerve (VN) is a key element of the autonomic nervous system. As a mixed nerve, the VN contributes to the bidirectional interactions between the brain and the gut, i.e., the brain‐gut axis. In particular, after integration in the central autonomic network of peripheral sensations such as inflammation and pain via vagal and spinal afferents, an efferent response through modulation of preganglionic parasympathetic neurons of the dorsal motor nucleus of the vagus and/or preganglionic sympathetic neurons of the spinal cord is able to modulate gastrointestinal nociception, motility, and inflammation. A low vagal tone, as assessed by heart rate variability, a marker of the sympatho‐vagal balance, is observed in functional digestive disorders and inflammatory bowel diseases. To restore a normal vagal tone appears as a goal in such diseases. Among the therapeutic tools, such as drugs targeting the cholinergic system and/or complementary medicine (hypnosis, meditation…), deep breathing, physical exercise, VN stimulation (VNS), either invasive or non‐invasive, appears as innovative. There is new evidence in the current issue of this Journal supporting the role of VNS in the modulation of gastrointestinal functions.     

Molecular hydrogen potentiates hypothermia and prevents hypotension and fever in LPS-induced systemic inflammation

Molecular hydrogen (H₂) exerts anti-oxidative, anti-apoptotic, and anti-inflammatory effects. Here we tested the hypothesis that H₂ modulates cardiovascular, inflammatory, and thermoregulatory changes in systemic inflammation (SI) induced by lipopolysaccharide (LPS) at different doses (0.1 or 1.5 mg/kg, intravenously, to induce mild or severe SI) in male Wistar rats (250–300 g). LPS or saline was injected immediately before the beginning of 360-minute inhalation of H₂ (2% H₂, 21% O₂, balanced with nitrogen) or room air (21% O₂, balanced with nitrogen). Deep body temperature (Tb) was measured by dataloggers pre-implanted in the peritoneal cavity. H₂ caused no change in cardiovascular, inflammatory parameters, and Tb of control rats (treated with saline). During mild SI, H₂ reduced plasma surges of proinflammatory cytokines (TNF-α and IL-6) while caused an increase in plasma IL-10 (anti-inflammatory cytokine) and prevented fever. During severe SI, H₂ potentiated hypothermia, and prevented fever and hypotension, which coincided with reduced plasma nitric oxide (NO) production. Moreover, H₂ caused a reduction in surges of proinflammatory cytokines (plasma TNF-α and IL-1β) and prostaglandin E₂ [(PGE₂), in plasma and hypothalamus], and an increase in plasma IL-10. These data are consistent with the notion that H₂ blunts fever in mild SI, and during severe SI potentiates hypothermia, prevents hypotension reducing plasma NO production, and exerts anti-inflammatory effects strong enough to prevent fever by altering febrigenic signaling and ultimately down-modulating hypothalamic PGE₂ production.     

Urocortin shares the memory modulating effects of corticotropin-releasing factor (CRF): mediation by CRF1 receptors

Intracerebroventricular (i.c.v.) administration of corticotropin-releasing factor (CRF) biphasically affects performance in tests of learning and memory. In the present study, we used CRF, urocortin (Ucn), a recently cloned CRF homologue, and CRF receptor antagonists, to determine which CRF receptor subtype(s) mediate the memory modulating effects of CRF receptor agonists in male Wistar rats. Under difficult learning conditions (massed trials), i.c.v. pretreatment with CRF or Ucn facilitated the acquisition of spatial navigation in the Morris water maze in a non-dose-dependent fashion (optimal doses of 0.1 and 0.03 microg, respectively). Under less difficult learning conditions (spaced trials), both peptides impaired water maze performance. In addition, with i.c.v. posttraining treatment, the peptides were equipotent (1.0 microg) in facilitating the consolidation of passive avoidance learning. The performance-enhancing effects of Ucn in both water maze and passive avoidance paradigms were reversed by i.c.v. pretreatment with D-Phe CRF(12-41) (2.5, 5 microg), a broad CRF(1)/CRF(2) receptor antagonist, or antalarmin (10 microg), a potent, nonpeptide, CRF(1) selective receptor antagonist. Thus, Ucn shares CRF's memory-modulating effects, and these effects appear to be mediated via the CRF(1) receptor. These findings are consistent with the hypothesis that CRF receptor agonists affect performance in tests of learning and memory by increasing arousal.     

Voxel-based analysis of confounding effects of age and dementia severity on cerebral metabolism in Alzheimer's disease

Alzheimer's disease is characterized by early hippocampal lesions, but neuropathological and functional imaging studies have also demonstrated involvement of associative cortices in patients suffering from this illness. New image-processing technologies have led to demonstration of predominant posteromedial cortical metabolic impairment in the disease. Confounding effects of both age and dementia severity on brain metabolism were assessed using categorical and correlational analyses performed with Statistical Parametric Mapping. Posterior cingulate and precuneus metabolism, assessed by positron emission tomography, was significantly correlated with age in a population of 46 patients with probable Alzheimer's disease. Metabolism in posterior cingulate and precuneus was higher in elderly than in younger patients with a diagnosis of Alzheimer's disease, even when dementia severity was taken as a confounding covariate. The data suggest that the sensitivity of positron emission tomography for the diagnosis of Alzheimer's disease is reduced in elderly cases, where less severe pathology is sufficient to induce clinical symptoms of dementia. Conversely, higher posteromedial metabolic impairment in early onset cases may reflect greater density of regional cerebral lesions or major decrease of functional afferences in a richly connected multimodal associative area. Posterior cingulate metabolism was also correlated to dementia severity, even when age was taken as a confounding covariate, whereas metabolism in the hippocampal formation was not shown to correlate with global cognitive deficit. Functional correlation was maintained between posterior cingulate and middle frontal cortex in demented patients as in elderly controls. The key role of posteromedial cortex in cognitive dysfunction assessed in Alzheimer's disease is probably related to its highly integrated position within attentional, visuospatial and memory neuronal networks.     

The effects of maternal inflammation on neuronal development: possible mechanisms

That maternal inflammation adversely affects fetal brain development is well established. Less well understood are the mechanisms that account for neurodevelopmental disorders arising from maternal inflammation. This review seeks to begin an examination of possible sites and mechanisms of action whereby inflammatory cytokines - produced by the mother or by the fetal brain - could impact the developing fetus. We focus first on the placenta where cytokines maintain the immunological environment that prevents maternal rejection of the fetus. Following a brief examination of placental transfer of maternal cytokines, the focus turns on embryonic microglia, early and ubiquitous residents of the developing brain. Finally, a more intense examination of interleukin-6 (IL-6) and bone morphogenetic proteins (BMPs) provides examples of glial- or maternal-derived cytokines that are known to have profound effects on developing systems and that could, if dysregulated, have undesirable consequences for brain development.     

Depressive type and state effects on personality measures

We examine the hypothesis that the effect of mood state on personality questionnaire scores is more a function of diagnosis than of depression severity. Sixteen endogenous and 83 neurotic depressives completed a battery of personality questionnaires at a baseline assessment and again 20 weeks later. Scores on the personality measures changed significantly. Endogenous depressives were found to have more pronounced changes on measures of dependence and timidity, but when change in mood state was partialed out only one of the dependence measures and timidity remained significant. Thus the hypothesis only received partial support--change in mood state appears to be the major factor in elevating personality questionnaire scores.     

Permanent cerebral hypoperfusion: 'preconditioning-like' effects on rat energy metabolism towards acute systemic hypotension

Chronic cerebrovascular disorders are often complicated by additional temporary ischaemic insults, resulting in substantial deterioration of brain energy metabolism. In the present study, chronic limitations of oxygen supply were induced in Wistar rats by 2 weeks of permanent bilateral common carotid artery occlusion (2-vo) to initiate a 'preconditioning-like' effect that protects rat brain energy metabolism against further acute systemic hypotension (15 min). Haemodynamic parameters, arterial blood gases and body temperature were monitored. Energy metabolites were determined in rat parietotemporal cerebral cortex: adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP), phosphocreatine (PCr), and adenosine by the high-pressure liquid chromatography (HPLC) technique and lactate spectrophotometrically. After 2 weeks, permanent 2-vo led to a significant decrease in the concentrations of cortical tissue ATP and PCr, from 3.06+/-0.48 to 2. 09+/-0.28 and from 4.27+/-0.63 to 3.35+/-0.41 micromol/g, respectively. These changes were associated with a two-fold increase in AMP and adenosine. Acute systemic hypotension alone (non-preconditioning) reduced ATP and PCr drastically, to 0.97+/-0. 51 and 1.76+/-1.23 micromol/g. Tissue concentrations of lactate, AMP, and adenosine were markedly increased, three- to five-fold, in 'non-preconditioned' brain tissue. In contrast, after 2 weeks of 2-vo acute hypotension did not significantly alter the cortical energy state any further. The effects of preconditioning on tissue ATP and PCr were most pronounced at 5 min and 48 h after reperfusion. In conclusion, permanent 2-vo seems to activate compensatory mechanisms, which effectively protect the rat's cortical energy metabolism against an additional ischaemic attack ('preconditioning-like' effect).     

Hormone effects on fMRI and cognitive measures of encoding: importance of hormone preparation

We compared fMRI and cognitive data from nine hormone therapy (HT)-naive women with data from women exposed to either opposed conjugated equine estrogens (CEE) (n = 10) or opposed estradiol (n = 4). Exposure to either form of HT was associated with healthier fMRI response; however, CEE-exposed women exhibited poorer memory performance than either HT-naive or estradiol-exposed subjects. These preliminary findings emphasize the need to characterize differential neural effects of various HTs.     

Injury severity and cell death mechanisms: effects of concomitant hypovolemic hypotension on spinal cord ischemia-reperfusion in rats

A number of previous studies indicated that ischemia-reperfusion injury causes two distinct types of cell death--necrosis and apoptosis--in the central nervous system. It was also implicated that the intensity of injury can somehow affect the cell death mechanisms. By occluding the descending thoracic aorta with or without simultaneously induced hypovolemic hypotension in rats, we established a model of experimental spinal cord ischemia-reperfusion (I/R) in which the injury severity can be controlled. Recordings of carotid blood pressure (CBP) and spinal cord blood flow (SCBF) showed that aortic occlusion induced dramatic CBP elevation but SCBF drop in both the normotensive (NT) and hypotensive (HT) groups of rats. However, the HT group demonstrated significantly lower SCBF during aortic occlusion, and much slower elevation of SCBF after reperfusion, and extremely poor neurological performance. Spinal cord lesions were characterized by infarction associated with extensive necrotic cell death, but little apoptosis and caspase-3 activity. In contrast, in the NT group, I/R injury resulted in minor tissue destruction associated with persistent abundant apoptosis, augmented caspase-3 activity, and favorable functional outcome. The relative sparing of motoneurons in the ventral horns from apoptosis might have accounted for the minor functional impairment in the NT group. The severity of I/R injury was found to have substantial impact on the histopathological changes and cell death mechanisms, which correlate with neurological performance. Our results implicate that injury severity and duration after injury are two critical factors to be considered in therapeutic intervention.     

Methylphenidate effects on global and complex measures of EEG.

Methylphenidate (MPH) effects on global and complex measures of electroencephalography were examined in boys with attention-deficit-hyperactivity disorder between the ages of 9 and 11 years. Electroencephalogram (EEG) data were collected separately from the administration of a continuous performance task and were evaluated for changes in overall frequency, coherence, phase, and asymmetry and against a referential database. MPH did not produce a clear change in EEG frequency measures compared with the task condition, although it did induce regional changes in the EEG and produced an improvement in task performance. In comparison against the referential database, MPH appeared to lessen the impact of abnormalities in EEG coherence, EEG phase, and EEG asymmetry on performance measures.     

A new automated method for rat sleep deprivation with minimal confounding effects on corticosterone and locomotor activity

The function of sleep in physiology, behaviour and cognition has become a primary focus of neuroscience. Its study inevitably includes experimental sleep deprivation designs. However, concerns exist regarding confounds like stress, increased locomotor activity levels, and decreased motivation to perform operant tasks induced by the methods employed. We here propose a novel procedure for sleep deprivation in rats and evaluate how it affects sleep, corticosterone concentration profiles, locomotor activity levels, and motivation to perform an operant task. Before, during and after 12h of total sleep deprivation by means of gradually increasing the rotation variability and the speed of a novel automated, two-compartment sleep deprivation device, sleep-wake states were assessed by electroencephalography (n=21), brain extracellular corticosterone concentrations using microdialysis (n=11), locomotor activity by infrared measurements (n=8), and operant performance using a fixed-interval-fixed-ratio task (n=16). Sleep was effectively prevented during the procedure; rats on average slept less than 1% of the time (0.8±0.2%, mean±standard error). Brain corticosterone concentrations were mildly increased during the procedure, but did not exceed normal peak concentrations. Locomotor activity was not only increased during the procedure, but also did not exceed the peak levels found during undisturbed wakefulness. Food restriction to 12 g/rat/day prevented sleep deprivation from reducing the motivation to perform an operant task. This novel procedure can be applied to sleep deprive rats in a highly effective way, while keeping corticosterone and locomotor activity within the normal range.     

Depressive symptoms and diet: their effects on prospective inflammation levels in the elderly

It has been reported that a Mediterranean-type diet in old age is protective against inflammation in Italians with depressive symptoms. In the present study, we explore this hypothesis in a non-Mediterranean, elderly sample, and further disentangle whether it is a Mediterranean diet per se or a healthy diet, in general, that confers this protective effect. The sample is a cohort of people born in 1936, who were assessed on diet and depressive symptoms at age 70. Inflammatory markers, C-reactive protein, fibrinogen and albumin, were collected at ages 70 and 73, while Interleukin-6 transferrin and ferritin were measured at the second time-point only. Controlling for confounding factors (e.g., CVD risk factors, medication) no interaction effect of depressive symptoms and Mediterranean diet was observed on inflammation. However, a main effect of Mediterranean diet on change in C-reactive protein was significant (β=-0.10, p=0.03), and so too was an effect of the 'Health Aware' diet on ferritin (β=-0.12, p=0.02). An interaction between depressive symptoms and a Health Aware diet on transferrin levels showed that there was an association between increased depressive symptoms and inflammation in those following a Health Aware diet. Our results indicate that there are advantages of a Mediterranean diet over a Health Aware diet with respect to the progression of inflammation in old age and that depressive symptoms compound inflammatory burden only for specific biomarkers and under specific dietary conditions unrelated to the Mediterranean diet.     

The accumulative effects of modifiable risk factors on inflammation and haemostasis

Various modifiable risk factors have been associated with inflammation and haemostasis, although the accumulative effects have not yet been examined. We therefore explored additive and independent associations of modifiable risk factors (smoking, alcohol, cholesterol, obesity, hypertension, physical activity) with inflammatory (CRP) and haemostatic (fibrinogen) markers. Data were collected from a sample of 7670 healthy asymptomatic participants (45.9% men, aged 46.2+/-15.6 years). A graded increase in the risk of inflammation (CRP> or =3 mg/L) with increasing numbers of modifiable risk factors was demonstrated (odds ratio for > or =4 risk factors=5.09, 95% CI, 3.96-6.55). Similar associations were found in relation to haemostasis. Central adiposity was the strongest independent predictor of inflammation (OR=3.45, 95% CI, 3.07-3.87) although smoking most strongly predicted haemostasis (OR=2.19, 95% CI, 1.94-2.48). These findings suggest that targeting multiple risk factors is likely to have the greatest benefit for cardiovascular prevention.     

The relation between MRI measures of inflammation and neurodegeneration in multiple sclerosis

Gadolinium-enhanced magnetic resonance imaging (MRI) and measures of brain volume have been extensively applied in large-scale studies to assess disease activity and irreversible tissue damage in multiple sclerosis (MS). Although histopathological studies of MS demonstrated that axonal transection occurs at sites of inflammatory changes, the correlation between brain tissue loss and gadolinium enhancement was found to be either absent or poor in virtually all in vivo MRI studies. This review discusses the reasons of this "inflammation/neurodegeneration mismatch" in MS and proposes possible strategies for a better in vivo characterization of the complex pathological process of this disease.     

Estrogen and brain inflammation: effects on microglial expression of MHC, costimulatory molecules and cytokines

To model the effects of estrogen on adaptive immunity in the brain, we examined the effects of 17beta-estradiol on microglial parameters related to antigen presentation and T cell activation. Specifically, the effects of 17beta-estradiol on basal and LPS-induced surface staining of Class I and II MHC, as well as CD40, CD80, CD86, CD152, CD28, CD8, CD11b, Fas, FasL, and also ERalpha and ERbeta, were examined in N9 microglial cells. Additionally, the effects of 17beta-estradiol on basal and LPS-induced release of cytokines (TNF-alpha, IFN-gamma, IL-2, IL-4, and IL-10) were determined. Data indicate that estrogen increases IL-10 while decreasing TNFalpha and IFNgamma release from resting and LPS-stimulated N9 cells. Additionally, LPS-induced surface staining of MHC Class I, CD40, and CD86 was significantly attenuated by estrogen pretreatment. The basal percentage of cells positive for MHC Class I and II, CD40, and CD152, Fas, and FasL was significantly decreased by estrogen exposure. However, CD8, CD86, CD11b, and CD28 were unaffected by estrogen, and CD80 cell surface staining significantly increased following estrogen exposure. Taken together, these data indicate that estrogen can significantly decrease components of adaptive immunity in microglial cells, and highlight the multi-faceted regulatory effects of estrogen on microglial parameters related to antigen presentation and T cell interaction.